Jana Sripati, Cramer Nicolai
Laboratory of Asymmetric Catalysis and Synthesis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
J Am Chem Soc. 2024 Dec 25;146(51):35199-35207. doi: 10.1021/jacs.4c11947. Epub 2024 Dec 10.
Asymmetric -heterocyclic carbene (NHC) organocatalysis is a cornerstone of synthetic organic chemistry. The emerging concept of single-electron NHC catalysis broadened the scope of C-C bond-forming reactions, facilitating the synthesis of a variety of attractive racemic compounds. However, the development of effective and selective chiral NHC catalysts for asymmetric radical-mediated reactions has been challenging. In this report, we introduce a family of highly tunable chiral thiazolium carbenes with three distinct positions for broad electronic and steric modulation featuring bulky chiral flanking groups. We demonstrate the catalytic efficacy of these chiral carbenes in an enantioselective SET-type three-component acyl-difluoroalkylation of olefins using a broad range of aldehydes and difluoroalkyl bromides. This method provides straightforward access to a diverse set of β-difluoroalkylated α-chiral ketones (65 examples) with an up to 87% yield and excellent enantioselectivities of up to >99:1 er. The utility of this methodology is further outlined by enantio- and diastereoselective late-stage modifications of pharmaceutically relevant compounds and selective twofold orthogonal acyl-difluoroalkylations of linchpin reagents.
不对称-杂环卡宾（NHC）有机催化是合成有机化学的基石。单电子NHC催化这一新兴概念拓宽了C-C键形成反应的范围，促进了各种有吸引力的外消旋化合物的合成。然而，开发用于不对称自由基介导反应的有效且选择性的手性NHC催化剂一直具有挑战性。在本报告中，我们介绍了一类高度可调谐的手性噻唑鎓卡宾，其具有三个不同位置，可通过庞大的手性侧翼基团进行广泛的电子和空间调节。我们展示了这些手性卡宾在使用多种醛和二氟烷基溴进行的烯烃对映选择性单电子转移（SET）型三组分酰基-二氟烷基化反应中的催化效果。该方法提供了直接获得各种β-二氟烷基化α-手性酮（65个实例）的途径，产率高达87%，对映选择性高达>99:1 er。通过对药物相关化合物的对映和非对映选择性后期修饰以及关键试剂的选择性双重正交酰基-二氟烷基化，进一步概述了该方法的实用性。
